There are currently no clinically approved therapies that specifically target autoimmune diseases, which affect up to 24 million Americans. Present-day treatments compromise efficacy with secondary side effects as a consequence of generalized immunosuppression. A strategy to overcome these problems is to design new immunotherapies that exploit the natural capacity of dendritic cells (DCs) to generate antigen-specific regulatory T cells (Tregs), which in turn can silence undesired immune responses. Recently, I have demonstrated in mice that distinct subsets of skin DCs specialize in the induction of disease-specific Tregs. My findings depart from the long-held paradigm assuming that all DC subsets have similar functions and provide strong evidence that engaging selected DC subsets in vivo has a high probability of success as a safe therapeutic approach for autoimmune disease. However, translating this mouse discovery into human therapeutics is a major challenge. Through unbiased, high-definition molecular profiling of all human skin DC subsets and quantitative comparisons of their Treg-inducing capabilities, I aim to move the field towards a rational design of improved DC-based therapies for autoimmune disorders. As the proposed research unfolds, I will design and generate new tools to target these specialized DC subsets in humans. This proposal is ideally suited for the New Innovator Award. First, it uses innovative state-of-the-art techniques, i.e., CyTOF and RNA- seq, to unravel the DC network in human skin. Second, it is based on an innovative concept, still unexplored in humans, that the generation of disease-protective Tregs can be achieved by a few specialized DC subsets. Finally, the ultimate goal of this proposal is to develop new technology to harness human DC subsets in disease. I anticipate that this study will provide the intellectual framework to enginee improved and much needed clinical treatments against autoimmune diseases.